Salinosporamide structure-activity studies

The structurally-related 7-lactams salinosporamide A 1, omuralide 2 and lactacystin 3, of bacterial origin, inhibit proteasome activity, and so are of interest as lead compounds for the development of anticancer agents. Barbara . M. Potts of Nereus Pharmaceuticals in San Diego has reported (J. Med. Chem. 2005,48,3684) a detailed structure-activity studies in this series, and E.J. Corey of Harvard University has prepared (J. Am. Chem. Soc. 2005,127, 8974, 15386) several interesting structural analogues. Susumi Hatakeyama of Nagasaki University, building on previous work in this area, has reported (J. Org. Chem. 2004, 69,7765) a synthesis of 2 and 3 from Tris. 

Macherla VR, Mitchell SS, Manam RR, Reed KA, Chao T-H, Nichoson B, Deyanat-Yazdi G, Mai B, Jensen PR, Fenical WF, Neuteboom STC, Lam KS, Palladino MA, Potts BCM (2005) Structure-Activity Relationship Studies of Salinosporamide A (NPI-0052), a Novel Marine Derived Proteasome Inhibitor. J Med Chem 48 3684... 

Salinosporamides are a family of y-lactam-p-lactone natural products discovered in 2003 with the isolation of salinosporamide A from Salinispora tropica obtained from marine sediment from the Bahamas and from depths as great as -1100 m. The complete structural assignment 86 to salinosporamide A was accomplished by spectral analysis and by a single-crystal X-ray diffraction study (Figure 4.41) [207]. The pronounced anticancer activity of 86, as a 20S proteasome inhibitor, with IC50 values... 

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